Endocrine toxicity in cancer patients treated with nivolumab or pembrolizumab: results of a large multicentre study.

INTRODUCTION: The immune checkpoint inhibitors (ICPIs) agents anti-T lymphocytes-associated antigen 4 (CTLA-4) and anti-programmed cell death protein-1 (PD-1) and its ligands (PD-L1/PD-L2) have opened a new scenario in the treatment of cancer. These agents can induce immuno-related adverse events (irAEs), which may affect the endocrine system. PURPOSE: The aim of this study was to analyze the occurrence and the course of endocrine irAEs in cancer patients treated with anti-PD-1 immunotherapy. METHODS: This was a retrospective, multicentre study, involving cancer patients treated with the PD-1 inhibitors nivolumab or pembrolizumab at reference Oncology Centres. One hundred and seventy-nine consecutive patients with different types of cancer (mostly non-small cell lung cancer, melanoma, kidney cancer) were included in the study. Patients had received nivolumab (70.9%) or pembrolizumab (29.1%) for 2-33 months. The study evaluated clinical data records until the established date of July 15, 2018. The primary end point was the assessment of endocrine toxicity and possible predictive factors. RESULTS: Endocrine toxicity occurred in 54 out of 179 patients (30.2%) and was related to thyroid dysfunction, with the exception of one case of diabetes mellitus. Thyroid toxicity occurred mostly within 2 months from the initiation of immunotherapy (83% of cases). A pre-existing thyroid dysfunction was a significant predictor of disease flare. CONCLUSIONS: Thyroid alterations are frequently associated with anti PD-1 treatment in cancer patients. Regular thyroid assessment should be performed, particularly in the first months of treatment and in patients with a pre-existing thyroid disease.

What is the prognostic impact of FDG PET in locally advanced head and neck squamous cell carcinoma treated with concomitant chemo-radiotherapy? A systematic review and meta-analysis.

PURPOSE: Evidence is conflicting on the prognostic value of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in head and neck squamous cell carcinoma. The aim of our study was to determine the impact of semiquantitative and qualitative metabolic parameters on the outcome in patients managed with standard treatment for locally advanced disease. METHODS: A systematic review of the literature was conducted. A meta-analysis was performed of studies providing estimates of relative risk (RR) for the association between semiquantitative metabolic parameters and efficacy outcome measures. RESULTS: The analysis included 25 studies, for a total of 2,223 subjects. The most frequent primary tumour site was the oropharynx (1,150/2,223 patients, 51.7%). According to the available data, the majority of patients had stage III/IV disease (1,709/1,799, 94.9%; no information available in four studies) and were treated with standard concurrent chemoradiotherapy (1,562/2,009 patients, 77.7%; only one study without available information). A total of 11, 8 and 4 independent studies provided RR estimates for the association between baseline FDG PET metrics and overall survival (OS), progression-free survival (PFS) and locoregional control (LRC), respectively. High pretreatment metabolic tumour volume (MTV) was significantly associated with a worse OS (summary RR 1.86, 95% CI 1.08-3.21), PFS (summary RR 1.81, 95% CI 1.14-2.89) and LRC (summary RR 3.49, 95% CI 1.65-7.35). Given the large heterogeneity (I2 > 50%) affecting the summary measures, no cumulative threshold for an unfavourable prognosis could be defined. No statistically significant association was found between SUVmax and any of the outcome measures. CONCLUSION: FDG PET has prognostic relevance in the context of locally advanced head and neck squamous cell carcinoma. Pretreatment MTV is the only metabolic variable with a significant impact on patient outcome. Because of the heterogeneity and the lack of standardized methodology, no definitive conclusions on optimal cut-off values can be drawn.

REGOMA-OSS: a large, Italian, multicenter, prospective, observational study evaluating the efficacy and safety of regorafenib in patients with recurrent glioblastoma.

BACKGROUND: In the randomized phase II REGOMA trial, regorafenib showed promising activity in patients with recurrent glioblastoma. We conducted a large, multicenter, prospective, observational study to confirm the REGOMA data in a real-world setting. PATIENTS AND METHODS: The major inclusion criteria were histologically confirmed diagnosis of glioblastoma according to the World Health Organization (WHO) 2016 classification and relapse after radiotherapy with concurrent/adjuvant temozolomide treatment, good performance status [Eastern Cooperative Oncology Group performance status (ECOG PS 0-1)] and good liver function. Regorafenib was administered at the standard dose of 160 mg/day for 3 weeks on/1 week off. Brain magnetic resonance imaging was carried out within 14 days before starting regorafenib and every 8-12 weeks. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate, disease control rate (DCR), safety and health-related quality of life. The Response Assessment in Neuro-Oncology (RANO) criteria were used for response evaluation and Common Terminology Criteria for Adverse Events (CTCAE) version 5 for assessment of adverse events (AEs). RESULTS: From September 2020 to October 2022, 190 patients with recurrent glioblastoma were enrolled from 30 cancer centers in Italy: their median age was 58.5 years [interquartile range (IQR) 53-67 years], 68% were male and 85 (44.7%) were in optimal clinical condition (ECOG PS 0). The number of patients taking steroids at baseline was 113 (60%); the second surgery was carried out in 39 (20.5%). O6-methylguanine-DNA methyltransferase (MGMT) was methylated in 80 patients (50.3%) and 147 (92.4%) of the patients analyzed had isocitrate dehydrogenase (IDH) wild type. The median follow-up period was 20 months (IQR 15.6-25.5 months). The median OS was 7.9 months ([95% confidence interval (CI) 6.5-9.2 months] and the median PFS was 2.6 months (95% CI 2.3-2.9 months). Radiological response was partial response and stable disease in 13 (7.3%) and 26 (14.6%) patients, respectively, with a DCR of 21.9%. The median number of regorafenib cycles per patient was 3 (IQR 2.0-4.0). Grade 3-4 drug-related adverse events were reported in 22.6% of patients. A dose reduction due to AEs was required in 36% of patients. No deaths were considered as treatment-related AEs. CONCLUSIONS: This large, real-world observational study showed similar OS with better tolerability of regorafenib in patients with relapsed glioblastoma compared with the REGOMA study.

Synchronous bilateral testicular germ cell tumour: case report and review of the literature.

We report a case of a 30 years old male affected by synchronous bilateral germ cell tumor with a history of unilateral cryptorchidism; the patient underwent surgical treatment followed by adjuvant radiotherapy on paraaortic and iliac lymphnodes. Patients with synchronous tumors usually present with a higher stage disease in contrast to those with unilateral testicular carcinoma, yet the prognosis remains equally favorable.

The impact of modern radiotherapy on long-term cardiac sequelae in breast cancer survivor: a focus on deep inspiration breath-hold (DIBH) technique.

INTRODUCTION: One of the most feared side effects of radiotherapy (RT) in the setting of breast cancer (BC) patients is cardiac toxicity. This side effect can jeopardize the quality of life (QoL) of long-term survivors. The impact of modern techniques of RT such as deep inspiration breath hold (DIBH) have dramatically changed this setting. We report and discuss the results of the literature overview of this paper. MATERIALS AND METHODS: Literature references were obtained with a PubMed query, hand searching, and clinicaltrials.gov. RESULTS: We reported and discussed the toxicity of RT and the improvements due to the modern techniques in the setting of BC patients. CONCLUSIONS: BC patients often have a long life expectancy, thus the RT should aim at limiting toxicities and at the same time maintaining the same high cure rates. Further studies are needed to evaluate the risk-benefit ratio to identify patients at higher risk and to tailor the treatment choices.

Tumor-associated macrophages (TAMs) modulate response to HER2-targeted agents in a humanized mouse model of breast cancer.

PURPOSE: Tumor-associated macrophages (TAM) may participate to antitumor activity of anti-HER2-targeted therapies (Pertuzumab, Trastuzumab) in breast cancers harbouring HER-2 overexpression through antibody-dependent phagocytosis. Additive antitumor effect of concurrent cytotoxic chemotherapies, including Paclitaxel, may be counterbalanced by alteration in TAM infiltrate. The aim of this study is to evaluate the role of TAM in tumor response to anti-HER2-targeted therapies and chemotherapy in an experimental model of HER2-amplified breast cancer. METHODS: A xenograft mouse model was built by subcutaneous injection of the SKBR-3 human HER2-amplified breast cancer cell line in Hu-CD34+ mice. Animals were randomized to receive weekly administration of Cremophor (control), Trastuzumab+Pertuzumab (TP), and Paclitaxel+Trastuzumab+Pertuzumab (PTP) with or without macrophage depletion with clodronate (C). At week 4, mice were euthanised and tumors were harvested for immunohistochemical analysis of TAM infiltration (RBP-J CD163 and CD68 for M1, M2, and overall TAM, respectively). RESULTS: Tumor size was significantly lower in mice treated with TP, PTP, and PTP+C as compared to control, while no meaningful difference was observed in the TP+C arm. Analysis of TAM infiltrate showed significantly lower CD68 and CD163 expression in PTP, TP+C, and PTP+C as compared to TP and control arm. RBP-J expression was significantly decreased in mice treated with clodronate depletion. CONCLUSIONS: Activity of TP is modulated by TAM infiltrate, that is inhibited by concurrent administration of Paclitaxel. To enhance the effect of anti-HER2-targeted therapies and minimize chemotherapy-related side effects, modulation of TAM should be considered in novel therapeutic combinations.

Stereotactic Re-irradiation in Recurrent Prostate Cancer after Previous Postoperative or Definitive Radiotherapy: Long-term Results after a Median Follow-up of 4 Years.

AIMS: In 2018, we published early results from a cohort of patients treated with stereotactic body radiotherapy (SBRT) after previous radiotherapy with definitive or postoperative intent. We sought to provide extended follow-up of this cohort to confirm the safety and efficacy of this approach in a real-world scenario. MATERIALS AND METHODS: Fifty patients affected by local relapse after previous definitive or postoperative radiotherapy were treated with SBRT. Treatment provided a total dose of 30 Gy in five fractions. Data about biochemical relapse-free survival (BRFS) and metastasis-free survival (MFS), together with adverse events, were analysed. Toxicity was reported according to Common Terminology Criteria for Adverse Events (CTCAE) score v.4.03. RESULTS: After a median follow-up of 48.2 months, the median BRFS was 43 months. A Gleason score >7 and concomitant androgen deprivation therapy were shown to be predictors of the worst BRFS (hazard ratio 2.42, 95% confidence interval 1.09-5.41, P = 0.02; hazard ratio 2.83, 95% confidence interval 1.17-6.8, P = 0.02, respectively). The median MFS was not reached; concomitant androgen deprivation therapy was confirmed to be predictive of the worst MFS (hazard ratio 4.75, 95% confidence interval 1.52-14.8, P = 0.007). Late grade 1 and 2 rectal and bladder toxicity occurred in three (6%) and 13 (26%) patients, respectively. One patient experienced both grade 3 acute and chronic bladder toxicity. CONCLUSION: Salvage SBRT re-irradiation after previous postoperative or definitive radiotherapy for local prostate cancer recurrence confirmed promising results in terms of oncological outcomes and the safety of this approach.

Pattern of Recurrence After Stereotactic Radiotherapy in Prostate Cancer Patients With Nodal Pelvic Relapse. A Multi-Institutional Retrospective Analysis.

AIMS: Currently, when nodal pelvic oligorecurrent disease is detected, no standard treatment option is recommended. One possible salvage option is nodal stereotactic body radiotherapy (SBRT). Here we analysed recurrence patterns after nodal SBRT in patients affected by pelvic oligometastatic relapse after radical prostatectomy, and androgen deprivation therapy (ADT)-free survival in this population. MATERIALS AND METHODS: Data on 93 patients consecutively treated in five different institutions for pelvic oligorecurrent disease were reviewed. Inclusion criteria were biochemical recurrence after radical prostatectomy and imaging showing three or fewer metachronous lymphoadenopathies under aortic bifurcation. Patients underwent SBRT on all sites of disease. Concomitant ADT was allowed. RESULTS: After a median follow-up of 20 months (interquartile range 11-41), 57 patients had post-SBRT radiological evidence of relapse, for a median disease-free survival (DFS) of 15 months (95% confidence interval 9-24). Concomitant ADT was administered in 20 patients (21.5%). Overall, eight (8.6%), 21 (22.6%) and 28 (30.1%) patients had prostate bed only, pelvic nodal or distant relapse, respectively. The median ADT-free survival was not reached. Concomitant ADT, International Society for Urologic Pathology pattern at diagnosis < or ≥3, time to relapse ≤ or >12 months, prostate-specific antigen at recurrence < or ≥1.10 ng/ml and prostate-specific membrane antigen staging were not significantly associated with DFS. After relapse, 42 patients (45.2%) received a second SBRT course. CONCLUSION: Nodal SBRT yielded encouraging DFS and ADT-free survival in this population. Only a minority of patients developed prostate bed recurrence, suggesting that local treatment may be safely avoided. A consistent percentage of patients could be managed with a second SBRT course.

Palliative radiotherapy in older adults with head and neck squamous cell carcinoma: A systematic review.

Locally advanced Head and neck squamous cell carcinoma (SCCHN) represents a common oncologic pathology in older adults (OA). While radiotherapy represents a cornerstone in this context, it is unclear what is the optimal radiation regimen for SCCHN in the palliative setting, especially for OA. This article addresses issues related to palliative radiotherapy (PRT) in this setting with a focus on treatment modalities and toxicity. We also explore the use of quality of life and geriatric assessment in this setting. Medline, Scopus and Embase databases were queried for articles in this setting. We included studies published from January 1, 2000 through June 1, 2020, that were independently evaluated by two authors. Analyzed endpoints were progression free survival (PFS), overall survival (OS) and PRT toxicities. The meta-analysis was performed using Stata v.14. A total of 33 studies were included in this meta-analysis. The pooled median OS is 7.7 months, 2-years OS was worse for higher radiation dose (p = 0.02). The pooled median PFS was 5.4 months, PFS was influenced by EQD2 (p = 0.01), with patients receiving an EQD2 < 40 Gy that presented a poorer outcome. Regarding acute toxicities, most common pooled G3 toxicities were mucositis (7%) and dysphagia (15%). Among late toxicity, most common G3 toxicity was dysphagia in 7% of patients. Radiotherapy should be the most effective palliative treatment in symptomatic SCCHN OA. A tailored approach, guided by geriatric tools, would be indicated to choose the right therapy.

Prospective assessment of AR splice variant and PSMA detection on circulating tumor cells of mCRPC patients: preliminary analysis of patients enrolled in PRIMERA trial (NCT04188275).

In our institution, a prospective observational trial testing micro-RNA (miRNA) and ARV7 mutational status in metastatic, castration resistant prostate cancer (mCRPC), is currently recruiting (PRIMERA trial, NCT04188275). A pre-planned interim analysis was performed when 50% of the planned accrual was reached. In this report, we explored the predictive value of Circulating Tumor Cell (CTC) detection in mCRPC patients undergoing 1st line therapy. Moreover, ARV7, ARFL, PSMA and PSA expression on CTC was reported to explore potential correlation with patient prognosis and response to therapy. PRIMERA is a prospective observational trial enrolling mCRPC patients undergoing standard treatment (ARTA + ADT) after I line ADT failure. Clinical and pathological features were collected. Outcomes selected for this preliminary analysis were time to castration resistance (TTCR), PSA at 8 weeks after ARTA therapy start, PSA drop at 8 weeks, Overall PSA drop, PSA nadir. Correlation between these outcomes and CTC detection was tested. Expression of ARV7, ARFL, PSA and PSMA was explored in CTC+ patients to assess their prevalence in this cohort and their impact on selected outcomes. Median TTCR was significantly shorter in CTC+ vs CTC- patients (32.3 vs 75 months, respectively, p = 0.03) and in ARFL+ vs ARFL- patients (30.2 vs 51.1 months, respectively, p = 0.02). ARV7, PSMA and PSA expression on CTC had no impact on median TTCR, nor on biochemical response to therapy. Patients in whom CTC and ARFL expression were detected had significant reduced TTCR. However, PSA response was not influenced by CTCs detection and specific biomarkers expression.

Will a tumor pandemic come after the COVID-19 pandemic? Head and Neck cancer perspective.

The COVID-19 pandemic demands a reassessment of head and neck oncology treatment paradigms by posing several challenges for oncology services, with unprecedented pressure on the regional health care system. Since February 2020 this has severely disrupted health-care services, leading to accumulating clinic caseload and substantial delays for operations. The head and neck cancer services have been faced with the difficult task of managing the balance between infection risk to health-care providers and the risk of disease progression from prolonged waiting times. Herein, we share our experience in Firenze (Italy) and propose our action plan on the management of head and neck cancer services via multi-institution collaboration.

Does a 6-point scale approach to post-treatment 18F-FDG PET-CT allow to improve response assessment in head and neck squamous cell carcinoma? A multicenter study.

PURPOSE: Response assessment to definitive non-surgical treatment for head and neck squamous cell carcinoma (HNSCC) is centered on the role of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET-CT) 12 weeks after treatment. The 5-point Hopkins score is the only qualitative system available for standardized reporting, albeit limited by suboptimal positive predictive value (PPV). The aim of our study was to explore the feasibility and assess the diagnostic accuracy of an experimental 6-point scale ("Cuneo score"). METHODS: We performed a retrospective, multicenter study on HNSCC patients who received a curatively-intended, radiation-based treatment. A centralized, independent qualitative evaluation of post-treatment FDG-PET/CT scans was undertaken by 3 experienced nuclear medicine physicians who were blinded to patients' information, clinical data, and all other imaging examinations. Response to treatment was evaluated according to Hopkins, Cuneo, and Deauville criteria. The primary endpoint of the study was to evaluate the PPV of Cuneo score in assessing locoregional control (LRC). We also correlated semi-quantitative metabolic factors as included in PERCIST and EORTC criteria with disease outcome. RESULTS: Out of a total sample of 350 patients from 11 centers, 119 subjects (oropharynx, 57.1%; HPV negative, 73.1%) had baseline and post-treatment FDG-PET/CT scans fully compliant with EANM 1.0 guidelines and were therefore included in our analysis. At a median follow-up of 42 months (range 5-98), the median locoregional control was 35 months (95% CI, 32-43), with a 74.5% 3-year rate. Cuneo score had the highest diagnostic accuracy (76.5%), with a positive predictive value for primary tumor (Tref), nodal disease (Nref), and composite TNref of 42.9%, 100%, and 50%, respectively. A Cuneo score of 5-6 (indicative of residual disease) was associated with poor overall survival at multivariate analysis (HR 6.0; 95% CI, 1.88-19.18; p = 0.002). In addition, nodal progressive disease according to PERCIST criteria was associated with worse LRC (OR for LR failure, 5.65; 95% CI, 1.26-25.46; p = 0.024) and overall survival (OR for death, 4.81; 1.07-21.53; p = 0.04). CONCLUSIONS: In the frame of a strictly blinded methodology for response assessment, the feasibility of Cuneo score was preliminarily validated. Prospective investigations are warranted to further evaluate its reproducibility and diagnostic accuracy.

TomoTherapy treatments of multiple brain lesions: an in-phantom accuracy evaluation.

Aim of the present study was to evaluate the accuracy which can be obtained with helical TomoTherapy® (HT, Accuray) systems in the case of multiple intracranial targets treatments. Set-up accuracy was measured, for different registration options and MegaVoltage CT (MVCT) slice thickness, by applying known misalignments to an ad-hoc developed phantom. End-to-end (E2E) tests were performed to assess the delivery accuracy in phantoms containing multiple targets by using radiochromic films: measured dose distribution centroids were compared with physical and calculated target positions on axial and coronal planes. A Gamma index analysis was carried out on planned and measured planar dose maps. The bone and tissue algorithm with the fine MVCT reconstruction grid gave the best results among the automatic options. The most accurate registration modality resulted to be the manual one with a sub-voxel accuracy shifts and a capability in the detection of rotations within 0.3°. For the E2E along the coronal plane (six targets), a mean deviation between measured dose distribution centroids and physical barycenters of 0.6 mm (range 0.1 mm-1.3 mm) was observed. Along the axial plane (five targets), a mean deviation of 1.2 mm (range 0.7 mm-2.1 mm) was found for the centroids shifts. Gamma index (5%, 1 mm, local) passing rates higher than 87.5% between planned and delivered dose distributions were measured. These results demonstrate that multiple brain lesion HT treatments are feasible with an accuracy at least comparable to frameless linac-based delivery, when a set-up capable to assure angular corrections and a reliable patient immobilization is employed.

Benefit of ablative versus palliative-only radiotherapy in combination with nivolumab in patients affected by metastatic kidney and lung cancer.

PURPOSE: Here, we present the results from a retrospective analysis, with the purpose of evaluating the safety and feasibility of nivolumab and radiotherapy (RT) concomitant association in metastatic kidney and lung cancer patients. MATERIALS AND METHODS: From August 2015 until September 2017, we retrospectively observed 20 patients with metastatic lung and renal cell carcinoma who had been initiated therapy with nivolumab and underwent concomitant RT. RT was administered either as an ablative therapy in the oligometastatic/oligoprogressive setting or as palliative-only treatment for symptomatic patients. Data on progression-free and overall survival (PFS and OS), treatment response and adverse events were collected and reported. Comparison between palliative-only and ablative treatments was performed. RESULTS: PFS and OS were 7 and 12.5 months in the entire population, respectively. Oligoprogressive patients treated with ablative intent, compared to patients undergoing RT with palliative-only intent, had statistically longer PFS (11.5 vs 5.2 months, HR 0.42, CI 0.18-0.98, p 0.03) and OS (17.9 vs 10.31 months, HR 0.41 CI 0.16-1.02, p 0.04). Considering only patients treated with ablative intent, 87.5% showed response to treatment, and complete response was reported in 37.5% of cases. Adverse G2-G3 related to combination treatment were reported as follows: 1 gastrointestinal (nausea), 4 breakthrough pain. CONCLUSIONS: Our data showed significant advantage for oligoprogressive patients treated with RT during nivolumab therapy. No safety alert emerged. These results underline the potential synergistic effects of RT and Immune therapy combination. Our analysis prompts further prospective studies exploring the benefit of integrated treatment strategies.

Stereotactic radiotherapy in oligoprogressive and oligorecurrent urothelial cancer patients: A retrospective experience.

Urothelial cancer is one of the most common malignancies; after relapse or disease progression available therapeutic options are limited. We analyze efficacy and toxicity of local treatment on metastases using stereotactic body radiation therapy (SBRT) in selected patients with oligometastatic disease from urothelial cancer. A significant percentage of treated lesions achieved local control, with a promising overall response rate. OBJECTIVES: to analyze efficacy and toxicity of local treatment on metastases using stereotactic body radiation therapy (SBRT) in selected patients with oligometastatic disease from urothelial cancer. MATERIALS AND METHODS: Data from clinical records of 19 patients treated in our institution since May 2011 to October 2017 with SBRT for oligometastatic/oligoprogressive urothelial carcinoma were retrospectively collected. Clinical outcomes in terms of local control (LC), response rate, symptoms control, progression free and overall survival (PFS and OS), and adverse events were analyzed and reported. RESULTS: Nineteen patients were treated on 25 metastatic lesions; 5 of them received treatment on multiple sites. After an average follow up of 11.5 months, LC was achieved in 17 lesions (68%) and there was no local recurrence in lesions with complete or partial response. OS was 13.8 months. Adverse events were reported only in 3 patients (5 overall events). No late toxicity was reported. CONCLUSIONS: An approach consisting in SBRT for local treatment of oligometastatic or persistent disease can be effective and safe in selected patients. Prospective studies are needed, to find correct selection criteria and optimal dose and fractionation.

Stereotactic body radiation therapy (SBRT) on renal cell carcinoma, an overview of technical aspects, biological rationale and current literature.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is characterized by the delivery of high doses of ionizing radiation in few fractions. It is highly effective in achieving local control, and, due to the high biological effective dose administered, it seems to overcome the radioresistance of renal cell carcinoma (RCC). Thus, SBRT could constitute a treatment option for the management of localized RCC in patients who are not surgical candidates. In this paper, we report an overview about data from the current evidence about SBRT in patients affected by localized RCC. MATERIALS AND METHODS: A non-systematic review was performed, including data from both retrospective and prospective studies focusing on the use of SBRT for localized RCC and its biological rationale. Furthermore, ongoing trials on this issue are reported. CONCLUSION: Currently, SBRT might be considered a treatment alternative in inoperable patients affected by primary RCC. Currently, dose-escalation to 48 Gy in 3-4 fractions are effective and well tolerated. Emerging role of immune therapies in RCC patients warrant further studies to explore interactions between SBRT and immune response.

Robotic Stereotactic Retreatment for Biochemical Control in Previously Irradiated Patients Affected by Recurrent Prostate Cancer.

AIMS: Robotic stereotactic body radiotherapy (rSBRT) to local recurrences emerged as a valuable option for exclusive local failure after prior external beam radiation therapy (EBRT) for localised prostate cancer. The aim of this study was to assess the efficacy and safety of rSBRT in patients experiencing locally recurrent prostate cancer after prior definitive or postoperative radiotherapy using the Cyberknife. MATERIALS AND METHODS: Data from 50 patients were retrospectively reviewed. Local recurrence was assessed by 18F-choline positron emission tomography and pelvic magnetic resonance imaging; a dose of 30 Gy was delivered in five fractions. Prostate-specific antigen (PSA) was assessed at 2 months, 6 months and every 4 months thereafter. Toxicity was assessed according to CTCAE v.4.03. RESULTS: All patients received prior EBRT. The median EQD2 total dose was 74 Gy (60-80 Gy). Eleven patients were receiving androgen deprivation after prior biochemical failure. At 6 months, 41 patients showed a median PSA decline of -77.1% (14.3-99.3%), whereas nine patients experienced a median PSA elevation of +58.7% (0-2300.0%). Biochemical relapse-free survival (BRFS) was 80.0%. Impaired BRFS was correlated with the high-risk category at diagnosis (P = 0.014, hazard ratio 5.61) and ongoing androgen deprivation (P = 0.025, hazard ratio 2.98). Neither clinical variables nor dosimetric parameters were found to be predictive for toxicity. CONCLUSION: Focal rSBRT can achieve durable remission in locally relapsing patients and systemic treatment can be postponed with acceptable toxicity. Accurate patient selection is mandatory to maximise disease control.

Role of perfusion CT in the evaluation of metastatic nodal tumor response after radiochemotherapy in head and neck cancer: preliminary findings.

OBJECTIVE: To assess changes of CT perfusion parameters (ΔPCTp) of cervical lymph node metastases from head and neck cancer (HNC) before and after radiochemotherapy (RT-CT) and their association with nodal tumor persistence. PATIENTS AND METHODS: Eligibility criteria included HNC (Stage III-IV) candidates for RT-CT. Patients underwent perfusion CT (PCT) at baseline 3 weeks and 3 months after RT-CT. Blood volume (BV), blood flow (BF), mean transit time (MTT) and permeability surface (PS) were calculated. PET/CT examination was also performed at baseline and 3 months after treatment for metabolic assessment. RESULTS: Between July 2012 and May 2016, 27 patients were evaluated. Overall, only 3 patients (11%) experienced tumor persistence in the largest metastatic lymph node. A significant reduction of all PCTp values (p<0.0001), except MTT (from 6.3 to 5.7 s; p=0.089), was observed at 3 weeks post-RT-CT compared to baseline. All PCTp values including MTT were significantly lower at 3-month follow-up compared to baseline (p<0.05). Moreover, a statistically significant association was observed between nodal tumor persistence and high BF values (p=0.045) at 3 months after treatment that did not occur for the other parameters. CONCLUSIONS: Our preliminary findings show that all PCTp except MTT are significantly reduced after RT-CT. High BF values at 3 months post-RT-CT are predictive of nodal tumor persistence.

Tumor-associated macrophages (TAMs) modulate response to HER2-targeted agents in a humanized mouse model of breast cancer

PurposeTumor-associated macrophages (TAM) may participate to antitumor activity of anti-HER2-targeted therapies (Pertuzumab, Trastuzumab) in breast cancers harbouring HER-2 overexpression through antibody-dependent phagocytosis. Additive antitumor effect of concurrent cytotoxic chemotherapies, including Paclitaxel, may be counterbalanced by alteration in TAM infiltrate. The aim of this study is to evaluate the role of TAM in tumor response to anti-HER2-targeted therapies and chemotherapy in an experimental model of HER2-amplified breast cancer.MethodsA xenograft mouse model was built by subcutaneous injection of the SKBR-3 human HER2-amplified breast cancer cell line in Hu-CD34+ mice. Animals were randomized to receive weekly administration of Cremophor (control), Trastuzumab+Pertuzumab (TP), and Paclitaxel+Trastuzumab+Pertuzumab (PTP) with or without macrophage depletion with clodronate (C). At week 4, mice were euthanised and tumors were harvested for immunohistochemical analysis of TAM infiltration (RBP-J CD163 and CD68 for M1, M2, and overall TAM, respectively).ResultsTumor size was significantly lower in mice treated with TP, PTP, and PTP+C as compared to control, while no meaningful difference was observed in the TP+C arm. Analysis of TAM infiltrate showed significantly lower CD68 and CD163 expression in PTP, TP+C, and PTP+C as compared to TP and control arm. RBP-J expression was significantly decreased in mice treated with clodronate depletion.ConclusionsActivity of TP is modulated by TAM infiltrate, that is inhibited by concurrent administration of Paclitaxel. To enhance the effect of anti-HER2-targeted therapies and minimize chemotherapy-related side effects, modulation of TAM should be considered in novel therapeutic combinations.

Impact of molecular subtypes classification concordance between preoperative core needle biopsy and surgical specimen on early breast cancer management: Single-institution experience and review of published literature.

BACKGROUND: Core needle biopsy (CNB) plays a crucial role as diagnostic tool for breast cancer (BC). The characterization of biomarkers status before surgical treatment is crucial when primary systemic therapy is a therapeutic option. The aim of this analysis was to report concordance between preoperative CNB and surgical specimen (SS) in evaluating biomarkers and molecular subtypes. METHODS: Data have been collected from a cohort of 101 patients affected by early BC treated at Careggi Florence University Hospital, between January 2014 and March 2015. The conformity between molecular subtype classification was tested using kappa (κ) test. RESULTS: Mean age was 57.5 years (range 29-86). There was concordance between the estrogen receptor (ER) assessment on CNB and SS in 95 cases (94.1%). Concordance of the progesterone receptor (PgR) assessment was observed in 89 cases (88.1%). Concordance for detecting immunohistochemistry-assessed BC molecular subtypes was 87.1% (κ = 0.78). Concerning Ki-67 evaluation, we report a concordance rate of 88.1% (κ = 0.68). The evaluation of luminal A plus luminal B/HER negative subgroup showed a κ-value of 0.65. CONCLUSIONS: CNB showed good accuracy in evaluating hormonal receptors status, HER2, and BC molecular subtypes. Evaluation of Ki67 status was less accurate than other biomarkers; therefore, we recommend that it should be detected both on CNB and SS samples, especially in hormonal positive HER2 negative tumors, in order to avoid a misclassification of tumor subtypes that could lead to an omission of potential effective systemic therapy.